Is ABCA7 p.Phe1390Leu (c.4168T>C) pathogenic?

ABCA7 p.Phe1390Leu (c.4168T>C) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-01). AlphaMissense: likely pathogenic (0.955); Ultra-rare (popmax 0.061%, nfe).

How common is ABCA7 p.Phe1390Leu (c.4168T>C) in the general population?

ABCA7 p.Phe1390Leu (c.4168T>C) is ultra-rare (popmax 0.061%, nfe) (gnomAD).

What do computational predictors say about ABCA7 p.Phe1390Leu (c.4168T>C)?

AlphaMissense predicts likely pathogenic (score 0.955) — an in-silico prediction, not a clinical call.

ABCA7 p.Phe1390Leu

c.4168T>C · rs112719199 · VCV2648894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.061%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.955	likely pathogenic · top 1% in ABCA7
REVEL	0.583	indeterminate
SaProt	LLR -3.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.061% European (non-Finnish) · 718/1,177,156 alleles

Filtering AF 0.0572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0558%

Overall 0.0472% 757/1,603,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.061%	1,639
Remaining individualsnot grpmax-eligible	0.0386%	2,593
African / African-American	0.0107%	9,353
Admixed American	0.00503%	19,878
Finnishnot grpmax-eligible	0.00347%	28,833
South Asian	0.00221%	45,247

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCA7
Protein: p.Phe1390Leu
Coding: c.4168T>C
MANE Select: NM_019112
dbSNP: rs112719199
Type: single nucleotide variant
Location: chr19:1055314 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 1390: an α-helix

Full ABCA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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ABCA7 p.Arg652Cys Uncertain significance ★★ ⚠ same type
ABCA7 p.Arg880Trp Uncertain significance ★★ ⚠ same type
ABCA7 p.Asp1452Asn Uncertain significance ★★ ⚠ same type
ABCA7 p.Asp2085Asn Uncertain significance ★★ ⚠ same type
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Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca7-p-phe1390leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown